In recent years, several conditions have been identified as risk factors for the development of Alzheimer's disease (AD). Two such risk factors are age-related testosterone loss in men and type 2 diabetes (T2D). It is unclear how these two conditions increase the risk for AD. Further, it is not known whether these conditions function as independent or related risk factors. In this application, we will evaluate the hypothesis that normal, age-related testosterone loss increases AD pathogenesis not only by direct effects on brain but also by promoting T2D. Similarly, we will investigate the complementary hypothesis that T2D increases AD pathology directly as well as by reducing testosterone levels. Thus, testosterone loss and T2D are postulated to be interrelated conditions that, in combination, cooperatively increase development of AD. Mechanistically, both low testosterone and T2D independently affect key features of AD neuropathology, including beta-amyloid accumulation, tau hyperphosphorylation, and inflammation. We hypothesize that testosterone and T2D cooperatively increase AD pathogenesis by interactions in the cell signaling pathways that regulate these three aspects of AD pathology. To investigate these hypotheses, we propose three specific aims. In Aim 1, we will investigate the effects of experimentally induced T2D on levels of testosterone and AD in animal models of aging and AD. In Aim 2, we will investigate the effects of experimentally-induced low testosterone on measures of T2D and AD in animal models of T2D. In both Aims 1 and 2, we will also examine the role of aging on identified relationships interactions between low testosterone and T2D. Finally, in Aim 3 we will evaluate candidate mechanisms underlying interactions between testosterone, focusing on signaling pathways that regulate beta-amyloid accumulation, tau hyperphosphorylation, and inflammation. Completion of our studies will characterize and mechanistically define relationships between testosterone and T2D and how they cooperatively act to promote development of AD, knowledge that will be invaluable in understanding and preventing AD in aging men.